HHS Public Access Author manuscript Author Manuscript

Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Pediatr Dermatol. 2016 November ; 33(6): e372–e374. doi:10.1111/pde.12961.

Prepubertal melanoma arising within a medium-sized congenital melanocytic nevus Leah Lalor, MD, University of Cincinnati, Department of Dermatology

Author Manuscript

Klaus Busam, MD, and Memorial Sloan Kettering Cancer Center Kara Shah, MD, PhD Cincinnati Children’s Hospital Medical Center, Division of Dermatology

Abstract We report a case of an 8-year old child who developed a 9.4mm-depth melanoma within a medium-sized congenital melanocytic nevus on the scalp. Genetic analysis revealed an activating NRAS Q61R mutation within the melanoma, which is more commonly associated with large or giant congenital melanocytic nevi. This case demonstrates that even a “low risk” congenital melanocytic nevus at a “low risk” age must be monitored regularly for the development of malignancy.

Author Manuscript

Keywords melanoma; congenital melanocytic nevus

CASE REPORT

Author Manuscript

An 8-year old Caucasian female with a medium-sized congenital melanocytic nevus (CMN) on the scalp (9 cm × 8 cm, predicted adult size of approximately 10 cm according to the categorization schema of Krengel, et al) (1) presented for evaluation of a single, 2 cm, heterogeneously pigmented nodule within the CMN that was noticed by her mother several months prior to presentation. Clinical monitoring had not been performed because her parents were previously told that there was no risk for the development of melanoma and that periodic examination was not necessary. The CMN was described as dark brown at birth, but had lightened significantly over time to the point where it was very faint and light brown in color.

Corresponding Author: Leah Lalor, [email protected], 3333 Burnet Ave, MLC 3004, Cincinnati, OH 45229, Phone: (513) 803-7835, Fax: (513) 636-5867. Consent for publication: All authors consent for publication of this manuscript Conflict of interest disclosure: None of the authors has any conflicts of interest. Statement of IRB approval and informed consent: Not applicable Notice of informed consent and releases: The parents of the child described in this report signed consent forms allowing publication of clinical photographs.

Lalor et al.

Page 2

Author Manuscript Author Manuscript

Due to concern for malignant degeneration, urgent excision was performed. Histopathology revealed an expansile nodular dermal proliferation of undifferentiated round cells without maturation (Figure 2); no lymphatic or perineural invasion or epidermal involvement were identified. The adjacent congenital nevus was composed of a predominantly intradermal epithelioid melanocytic proliferation with maturation with depth, wrapping around adnexal structures and extending into the subcutis; no mitoses were seen in the precursor nevus (Figure 3). Single nucleotide polymorphism (SNP) microarray revealed numerous chromosomal aberrations, including mosaic monosomy involving multiple chromosomes, deletion of 1p36, and duplication of 1q23, 8q24 and 6p25. These results were felt to be consistent with a diagnosis of a nodular melanoma arising within a CMN. Tumor thickness was 9.4mm, Clark level 5, without ulceration, with a mitotic rate of 8/mm2, and without perineural or vascular invasion. Re-excision with split thickness skin grafting and sentinel lymph node biopsy was performed. All surgical margins were negative, and 2/2 sentinel lymph nodes excised from the left preauricular and posterior cervical chains were negative. All imaging performed, including PET, brain MRI, abdominal and pelvic MRI, and chest CT, was negative for evidence of metastatic disease. Genomic profiling by next-generation sequencing identified NRAS Q61R mutation, MYC amplification, and MLL2 rearrangement at exon 51. Neither a BRAF nor a KIT mutation was identified. No adjuvant therapy was recommended by Oncology. She is currently doing well 12 months after diagnosis with no signs of recurrence, though the period of follow-up is too short to draw any conclusions regarding long-term prognosis.

DISCUSSION

Author Manuscript

Activating NRAS mutations, often involving codon 61, are commonly seen in large or giant CMN with a prevalence of up to 95% depending on the sensitivity of the assay, while the prevalence of BRAF mutation is significantly lower (~ 5–10%) (2–6). Small and medium CMN less frequently manifest NRAS mutations, which are seen in about 30%, but more commonly demonstrate BRAF mutations, with a prevalence of about 70% (2–4, 6, 7). Activated NRAS signaling occurs through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The PI3K/AKT pathway increases cell proliferation, promotes melanocyte survival, and stimulates directional migration; along with activation of NRAS, activation of this pathway is common in melanoma (8). Aberrant signaling through the PI3K/AKT pathway may predispose CMN with an activating NRAS mutation to malignant degeneration. We are aware of one published report of a melanoma arising within a medium-sized CMN with a documented activating NRAS mutation in a 29year old male (9).

Author Manuscript

Although the true lifetime risk of melanoma developing within a small- or medium-sized CMN is unknown due to the inherent limitations on conducting an informative prospective study, the risk is estimated to be less than 1% over a lifetime (10, 11). Although most commonly developing after puberty, melanoma arising within a small- or medium-sized CMN has been reported in younger children (12, 13). Differentiation from a proliferative nodule may be challenging. Proliferative nodules arising within large or giant CMN may develop at any age but most commonly arise in the first year of life. In proliferative nodules, evaluation for the presence of copy number alterations by array-CGH (comparative genomic Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01.

Lalor et al.

Page 3

Author Manuscript

hybridization) or SNP array generally results in either a normal genomic profile or the presence of whole chromosomal copy number aberrations, as opposed to the complex partial chromosomal aberrations typical of melanoma (14, 15). In addition, the histopathological characterization of a proliferative nodule is most commonly of a melanocytic proliferation composed of large spindled, nevoid, or epithelioid cells without atypia (5, 14). This case is a sobering reminder of the need for continued vigilance in monitoring congenital melanocytic nevi of all sizes. While the overall risk for malignant degeneration in small- and medium-sized CMN is quite low, and while spontaneous lightening of CMN may be noted, particularly on the scalp, melanoma may develop at any age, including prepubertal children. Clinicians and caregivers should be aware of this risk in order to allow for informed decision-making regarding management.

Author Manuscript

Acknowledgments The authors would like to thank Katharine Hanlon for the clinical images and Dr. Kerith Spicknall for the photomicrographs. The P30 CA008748 (NIH funding, core grant) is associated with Klaus Busam.

References

Author Manuscript Author Manuscript

1. Krengel S, Scope A, Dusza SW, Vonthein R, Marghoob AA. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol. 2013; 68:441–51. [PubMed: 22982004] 2. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007; 127:179–82. [PubMed: 16888631] 3. Charbel C, Fontaine RH, Malouf GG, Picard A, Kadlub N, El-Murr N, et al. NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J Invest Dermatol. 2014; 134:1067–74. [PubMed: 24129063] 4. Dessars B, De Raeve LE, Morandini R, Lefort A, El Housni H, Ghanem GE, et al. Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis. J Invest Dermatol. 2009; 129:139–47. [PubMed: 18633438] 5. Phadke PA, Rakheja D, Le LP, Selim MA, Kapur P, Davis A, et al. Proliferative nodules arising within congenital melanocytic nevi: a histologic, immunohistochemical, and molecular analyses of 43 cases. Am J Surg Pathol. 2011; 35:656–69. [PubMed: 21436676] 6. Salgado CM, Basu D, Nikiforova M, Bauer BS, Johnson D, Rundell V, et al. BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi. Pediatr Dev Pathol. 2015; 18:1–9. [PubMed: 25490715] 7. Ichii-Nakato N, Takata M, Takayanagi S, Takashima S, Lin J, Murata H, et al. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J Invest Dermatol. 2006; 126:2111–8. [PubMed: 16691193] 8. Davies MA. The role of the PI3K-AKT pathway in melanoma. Cancer J. 2012; 18:142–7. [PubMed: 22453015] 9. Kiyohara T, Takata M, Itoh H, Kawami K, Ido H, Ishida H, et al. Malignant melanoma arising from an NRAS-mutated medium-sized congenital melanocytic nevus. J Dermatol. 2012; 39:1034–5. [PubMed: 22452623] 10. Sahin S, Levin L, Kopf AW, Rao BK, Triola M, Koenig K, et al. Risk of melanoma in mediumsized congenital melanocytic nevi: a follow-up study. J Am Acad Dermatol. 1998; 39:428–33. [PubMed: 9738777] 11. Swerdlow AJ, English JS, Qiao Z. The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol. 1995; 32:595–9. [PubMed: 7896948] 12. De Raeve L, Danau W, De Backer A, Otten J. Prepubertal melanoma in a medium-sized congenital naevus. Eur J Pediatr. 1993; 152:734–6. [PubMed: 8223803]

Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01.

Lalor et al.

Page 4

Author Manuscript

13. Neuhold JC, Friesenhahn J, Gerdes N, Krengel S. Case reports of fatal or metastasizing melanoma in children and adolescents: a systematic analysis of the literature. Pediatr Dermatol. 2015; 32:13– 22. [PubMed: 25487565] 14. Yelamos O, Arva NC, Obregon R, Yazdan P, Wagner A, Guitart J, et al. A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children. Am J Surg Pathol. 2015; 39:405–15. [PubMed: 25517953] 15. Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol. 2002; 161:1163–9. [PubMed: 12368190]

Author Manuscript Author Manuscript Author Manuscript Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01.

Lalor et al.

Page 5

Author Manuscript Author Manuscript Author Manuscript

Figure 1.

Clinical photograph from day of presentation showing a tumor within a faint congenital melanocytic nevus.

Author Manuscript Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01.

Lalor et al.

Page 6

Author Manuscript Author Manuscript Author Manuscript

Figure 2.

High power photomicrograph of round cells with vesiculated nuclei, prominent nucleoli, scant cytoplasm, overall paucity of pigment, and many abnormal mitotic figures (original magnification ×40).

Author Manuscript Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01.

Lalor et al.

Page 7

Author Manuscript Author Manuscript Author Manuscript

Figure 3.

Low power photomicrograph demonstrating sheets of tumor cells abutting a banal congenital melanocytic nevus component with sharp demarcation between malignant tumor and benign nevus (original magnification ×2).

Author Manuscript Pediatr Dermatol. Author manuscript; available in PMC 2017 November 01.

Prepubertal Melanoma Arising within a Medium-Sized Congenital Melanocytic Nevus.

We report the case of an 8-year-old child who developed a 9.4-mm-deep melanoma within a medium-sized congenital melanocytic nevus on the scalp. Geneti...
675KB Sizes 2 Downloads 8 Views